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Biomedical subjects

A Hamsten

Publications and source records attributed to A Hamsten.

At least 37 records · Page 2Linked to original sources
PubMed2004

Sex hormone--binding globulin--a surrogate marker for the prothrombotic effects of combined oral contraceptives.

OBJECTIVE: The purpose of this study was to investigate the plausibility of serum sex hormone-binding globulin (SHBG) concentration as a risk marker for venous thromboembolism (VTE) during use of combined oral contraceptives (COC). Study design This was a prospective, randomized cross-over study. Thirty-five women were treated with COCs containing the same amount of ethinyl estradiol and either levonorgestrel (LNG/EE) or desogestrel (DG/EE). Serum SHBG and markers of hemostasis were determined before and after 2 months on each treatment. RESULTS: SHBG increased significantly with both preparations. Treatment with DG/EE caused more pronounced prothrombotic changes in hemostatic parameters than LNG/EE. With both treatment regimens, there was a significant correlation between changes in resistance to activated protein C (APCr) and changes in plasma SHBG. CONCLUSION: The correlation between SHBG and the well-established risk factor APCr might indicate the usefulness of SHBG as a risk marker for VTE during COC treatment.

Adolescent↗
PubMed2004

Abnormal glucose tolerance--a common risk factor in patients with acute myocardial infarction in comparison with population-based controls.

BACKGROUND: A high prevalence of newly detected diabetes and impaired glucose tolerance (abnormal glucose tolerance) was recently reported in patients with acute myocardial infarction. It is important to verify whether this finding is specific for the patients or attributable to the population, from which they were recruited. OBJECTIVE: To verify whether abnormal glucose tolerance is more prevalent in patients than in controls chosen from the same population and to compare metabolic characteristics between the two groups. DESIGN AND SUBJECTS: The metabolic state was assessed in patients (n = 181) admitted with acute myocardial infarction and no history of diabetes before discharge and after 3 months. Sex- and age-matched controls (n = 185) without previously known diabetes or cardiovascular disease except hypertension were recruited from the general population. MAIN OUTCOME MEASURES: Oral glucose tolerance test, glucosylated haemoglobin A1c (HbA1c), insulin, proinsulin, lipid profile, fibrinolytic function and inflammatory markers. RESULTS: Abnormal glucose tolerance was more common (number/all classified) in patients at discharge 113/168 (67%) and after 3 months 95/145 (66%) than in controls 65/185 (35%) (P < 0.001). Dyslipidaemia (70% vs. 29%; P < 0.001) and previously treated hypertension (32% vs. 18%; P = 0.028) were more frequent amongst patients whilst obesity (18% vs. 24%) did not differ significantly. Blood glucose, HbA1c, proinsulin, proinsulin/insulin ratio, triglycerides, insulin resistance (by HOMA) and fibrinogen were consistently higher in patients than controls (P < 0.01). CONCLUSIONS: Abnormal glucose tolerance was almost twice as common amongst patients with acute myocardial infarction as in matched controls. Impaired glycaemic control accompanied by insulin resistance, dyslipidaemia, hypertension, together with increased plasma fibrinogen and proinsulin levels were main features characterizing patients.

Acute Disease↗
PubMed2004

Genetic and structural evaluation of fatty acid transport protein-4 in relation to markers of the insulin resistance syndrome.

Disturbances in fatty acid metabolism are involved in the etiology of insulin resistance and the related dyslipidemia, hypertension, and procoagulant state. The fatty acid transport proteins (FATPs) are implicated in facilitated cellular uptake of nonesterified fatty acids (NEFAs), thus potentially regulating NEFA concentrations and metabolism. The aim of this study was to investigate polymorphic loci in the FATP4 gene with respect to associations with fasting and postprandial lipid and lipoprotein variables and markers of insulin resistance in 608 healthy, middle-aged Swedish men and to evaluate possible mechanisms behind any associations observed. Heterozygotes for a Gly209Ser polymorphism (Ser allele frequency 0.05) had significantly lower body mass index and, correcting for body mass index, significantly lower triglyceride concentrations, systolic blood pressure, insulin concentrations, and homeostasis model assessment index compared with common homozygotes. A three-dimensional model of the FATP4 protein based on structural and functional similarity with adenylate-forming enzymes revealed that the variable residue 209 is exposed in a region potentially involved in protein-protein interactions. Furthermore, the model indicated functional regions with respect to NEFA transport and acyl-coenzyme A synthase activity and membrane association. These findings propose FATP4 as a candidate gene for the insulin resistance syndrome and provide a structural basis for understanding FATP function in NEFA transport and metabolism.

Amino Acid Sequence↗
PubMed2003

Gene expression and intracellular pathways involved in endothelial dysfunction induced by VLDL and oxidised VLDL.

OBJECTIVES: The molecular mechanisms underlying the relationship between elevated plasma concentrations of triglyceride-rich lipoproteins and coronary artery disease remain uncertain. In the present work, we investigated the gene expression pattern and intracellular pathways in human endothelial cells incubated with very low density lipoproteins (VLDL). Moreover, as VLDL can enter the arterial wall and undergo oxidative modification, we compared the VLDL-induced expression pattern with the one of oxidised VLDL (Ox-VLDL). METHODS: Total RNA from endothelial cells incubated with 75 microg/ml VLDL or Ox-VLDL and total RNA from endothelial cells under basal conditions were hybridised to identical microarrays containing 8411 genes. Seven clusters of expression profiles were identified. This pattern was validated by quantitative real-time PCR of selected genes. The intracellular pathway involved in VLDL or Ox-VLDL mediated endothelial responses were also investigated. RESULTS AND CONCLUSION: VLDL predominantly activated the ERK1/2 pathway while P38 MAPK was the main target of Ox-VLDL. CREB and NF-kappa B were activated by both VLDL and Ox-VLDL. Real-time PCR demonstrated that VLDL induced matrix metalloproteinase-2 (5.47+/-1.74 fold), CD38 (2.38+/-0.23) and transforming growth factor-alpha (2.51+/-0.30) expression. Ox-VLDL was found to induce interleukin-15 (2.10+/-0.48) and macrophage migration inhibitory factor (3.19+/-0.07) expression. In addition, several genes implicated in endothelial cell activation and damage/proliferation were identified by the array analysis. Ox-VLDL was found to promote the generation of reactive oxygen species and exert a cytotoxic effect, while VLDL lacks these effects. These findings confirm the involvement of VLDL and Ox-VLDL in endothelial dysfunction and suggest new genes and molecular mechanisms involved in these actions.

Cell Death↗
PubMed2003

A common polymorphism in the fatty acid transport protein-1 gene associated with elevated post-prandial lipaemia and alterations in LDL particle size distribution.

The fatty acid transport proteins (FATPs) have been implicated in facilitated cellular uptake of non-esterified fatty acids (NEFAs), thus having the potential to regulate local and systemic NEFA concentrations and metabolism. Hypothesising that genetic variation within the FATP genes may affect lipid metabolism, we investigated a G/A substitution at position 48 in intron 8 of the fatty acid transport-1 (FATP1) gene with respect to associations with fasting and post-prandial plasma lipid and lipoprotein variables in 628 healthy 50-year-old Swedish men and 426 Swedish women, aged 37-65 years. A subset of 105 men with the apoE3/E3 genotype underwent an oral fat tolerance test. Although fasting plasma TG concentrations were not different, male A/A individuals had significantly higher post-prandial TG concentrations and VLDL(1) (S(f) 60-400 apoB100)-to-VLDL(2) (S(f) 20-60 apoB100) ratio compared to male G/A and G/G individuals. A/A individuals apparently failed to suppress plasma NEFA concentrations during the oral fat tolerance test. Furthermore, fasting plasma concentrations of the largest, most buoyant LDL subfraction (LDL-I) were significantly lower in carriers of the A allele in the male cohort. Electromobility shift assays and reporter gene studies indicated that binding of nuclear factors and effect on transcriptional activity differ between the intron 8 alleles. These findings suggest that through regulation of NEFA trafficking, FATP1 might play a role in post-prandial lipid metabolism and development of cardiovascular disease.

Adult↗
PubMed2003

In vitro and in vivo lipolysis of plasma triglycerides increases the resistance to oxidative modification of low-density lipoproteins.

BACKGROUND: The majority of studies on low-density lipoprotein (LDL) particle size and susceptibility to oxidative modification have been either descriptive or interventional, but there are few mechanistic studies. MATERIALS AND METHODS: Effects of exhaustive in vitro and in vivo lipolysis of serum and plasma triglycerides, respectively, by lipoprotein lipase (LPL) were investigated in healthy normotriglyceridemic men. The LDL end-product of lipolysis of very low-density lipoprotein (VLDL) underwent compositional analysis, gradient gel electrophoresis and an assessment of resistance to copper-induced oxidative modification. RESULTS: The LDL particle contents of free fatty acid and alpha-tocopherol increased, whereas the contents of free and esterified cholesterol, alpha-carotene and coenzyme Q10 decreased upon incubation of serum with LPL in vitro. The LDL particle size decreased and the resistance to the oxidative modification of LDL increased. Lipolysis of plasma triglycerides in vivo, achieved by intravenous injection of heparin, did not alter the LDL particle size but increased the resistance to the oxidative modification of LDL. This change was accompanied by an increase in the LDL particle content of alpha-tocopherol, whereas the free fatty acid content was unaltered. CONCLUSIONS: The results show that the increased resistance to oxidative modification of LDL after lipolysis of plasma triglycerides was concomitant with an increased LDL particle content of alpha-tocopherol, and that free fatty acids did not seem to contribute to the increased resistance to oxidative modification of LDL in vivo. Furthermore, our data indicate that the resistance of LDL to oxidative modification is not dependent on particle size.

Aged↗
PubMed2003

Prognostic value of plasma C-reactive protein and fibrinogen determinations in patients with acute myocardial infarction treated with thrombolysis.

OBJECTIVES: To investigate the prognostic value of plasma C-reactive protein (CRP) and fibrinogen determinations in patients with acute myocardial infarction treated with thrombolysis. DESIGN: Longitudinal study of morbidity and mortality. SETTING: Coronary care unit at Danderyd Hospital, Stockholm, Sweden. SUBJECTS: A total of 222 patients aged 75 years or below, treated with thrombolysis because of typical symptoms of myocardial infarction and electrocardiogram showing ST-segment elevation or bundle branch block were included in the study. The patients were followed for 24-60 months (mean 40 +/- 16 months). MAIN OUTCOME MEASURES: Cardiovascular death or new myocardial infarction. RESULTS: Concentrations of CRP were significantly higher at 48 h than at 3 months, whilst the levels of fibrinogen were similar. CRP and fibrinogen concentrations measured during the acute phase of myocardial infarction were associated with cardiovascular death or a new myocardial infarction during follow-up in univariate analysis. CRP levels measured 3 months after the acute event were not associated with subsequent events whereas fibrinogen concentrations showed a borderline prognostic significance (P = 0.05). When CRP and fibrinogen were entered into multivariate analysis together with the previously established prognostic factors in the patient group (age, diabetes mellitus and left ventricular function), these markers of inflammation did not add further prognostic information. CONCLUSION: C-reactive protein and fibrinogen do not carry the same independent prognostic information after acute myocardial infarction treated with thrombolysis as in studies previously reported for patients with unstable angina or non-Q-wave myocardial infarction.

Aged↗
PubMed2003

The plasminogen activator inhibitor-1 -675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH study.

UNLABELLED: Although the potential role of plasminogen activator inhibitor-1 (PAI-1) in the development of coronary artery disease is strongly supported by its biological characteristics, results of clinical studies remain controversial. OBJECTIVES: To investigate whether plasma PAI-1 concentrations and the -675 4G/5G polymorphism located in the PAI-1 gene could constitute risk markers for myocardial infarction (MI). PATIENTS AND METHODS: We used a European case-control study, the HIFMECH study, comparing 598 men with MI and 653 age-matched controls. RESULTS: Insulin resistance explained a major part of the variation in PAI-1 (24%) whereas inflammation had only a minor contribution (0.01%). For both cases and controls plasma PAI-1 concentrations were significantly higher in the North than the South, and in both regions were higher in individuals with MI compared with control subjects [overall odds ratio (OR) for a 1 SD increase=1.54, 95% confidence interval (CI) 1.34, 1.77]. This difference was observed in all the centers studied. Overall, the difference between cases and control subjects remained significant after controlling for inflammation variables (OR=1.30, 95% CI 1.08, 1.57), but lost significance after controlling for insulin resistance variables (OR=1.17, 95% CI 0.98, 1.40). The 4G allele was associated with significantly higher PAI-1 levels in cases but not controls and, taken independently, did not modify the risk of MI (P=0.9). However, a significant interaction was observed with both insulin or proinsulin and the risk of MI (P=0.05 and 0.02, respectively), but not with triglycerides or body mass index (BMI). The insulin or proinsulin effect on risk was observed only in the carriers of the 4G/4G genotype. This interaction appeared not to be mediated by plasma PAI-1 antigen concentrations (P=0.01 and 0.02 after adjustment for PAI-1 plasma levels). The interaction with proinsulin but not insulin remained statistically significant after further adjustment for other factors associated with insulin resistance (triglycerides and BMI) and C-reactive protein (P=0.01). CONCLUSION: This study suggests that PAI-1 has a role in risk of MI in the presence of underlying insulin resistance. A significant interaction between insulin or proinsulin and the -675 4G/5G polymorphism was observed in risk for MI. The mechanisms for these interactions remain to be determined.

Case-Control Studies↗
PubMed2003

Peroxisome proliferator activated receptor delta genotype in relation to cardiovascular risk factors and risk of coronary heart disease in hypercholesterolaemic men.

OBJECTIVES: Peroxisome proliferator activated receptor delta (PPARD) is a transcription factor implicated in the regulation of genes involved in cholesterol metabolism. We recently discovered a common polymorphism in the 5'-untranslated region (5'-UTR) of the human PPARD, +294T/C, that is associated with an increased plasma low-density lipoprotein cholesterol (LDL-C) concentration in healthy subjects. Whether the +294C allele is associated with LDL-C elevation independently of the background lipoprotein phenotype and whether it confers increased risk of coronary heart disease (CHD) is unknown. Against this background, we investigated the relationships between the PPARD polymorphism and plasma lipoprotein concentrations and the risk for contracting CHD in the West of Scotland Coronary Prevention Study (WOSCOPS). DESIGN: A nested case-control study of participants in a randomized double-blind placebo-controlled trial of pravastatin in mildly-to-moderately hypercholesterolaemic men. SUBJECTS: A total of 580 cases of incident CHD and 1160 individuals who remained free of CHD (controls). MAIN OUTCOME MEASURES: Plasma lipoprotein concentrations and risk of CHD according to PPARD genotype. RESULTS: Individuals carrying the rare PPARD +294C allele had a significantly lower high-density lipoprotein cholesterol (HDL-C) concentration than subjects homozygous for the common T-allele. Homozygous carriers of the C-allele also showed a tendency towards higher risk of CHD compared with homozygous carriers of the T-allele. In addition, a gene-gene interaction involving the PPARD polymorphism and the PPAR alpha L162V polymorphism may influence the plasma LDL-C concentration. CONCLUSIONS: PPARD plays a role in cholesterol metabolism in man.

Anthropometry↗
PubMed2003

TNF-alpha: a link between hypertriglyceridaemia and inflammation in SLE patients with cardiovascular disease.

Patients with systemic lupus erythematosus (SLE) are at high risk of cardiovascular disease (CVD). Tumour necrosis factor-alpha (TNF-alpha) has been implicated in the pathophysiological processes of both SLE and CVD. This study focuses on the role of TNF-alpha and its soluble receptors in SLE-related CVD. In summary, 26 women (52 +/- 8.2 years) with SLE and a history of CVD (SLE cases) we compared with 26 age-matched women with SLE and no clinical manifestations of CVD (SLE controls) and 26 age-matched population-based control women (population controls). Plasma concentrations of circulating TNF-alpha, TNF-alpha receptor 1 (sTNFR1) and TNF-a receptor 2 (sTNFR2) were determined by ELISA. TNF-alpha, sTNFR1 and sTNFR2 were raised in SLE cases as compared to SLE controls (P = 0.009; P = 0.001; P = 0.001, respectively), and SLE controls had higher levels than population controls (P = 0.001; P = 0.02; P = 0.001, respectively). Exclusively in the SLE case group there was a striking positive correlation between TNF-alpha and plasma triglycerides (r = 0.57, P < 0.002), VLDL triglycerides (r = 0.54, P = 0.004) and VLDL cholesterol (r = 0.58, P = 0.002). Furthermore, TNF-alpha correlated with the waist-hip ratio but not with estimated insulin resistance. TNF-alpha may thus be a major factor in SLE-related CVD acting both by contributing to hypertriglyceridaemia and by promoting atherosclerosis-related inflammation. sTNFR1 and sTNFR2 are strongly associated with CVD in SLE but their exact roles in disease development remain to be elucidated.

Autoantibodies↗
PubMed2002

Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe.

The thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently described inhibitor of fibrinolysis that decreases plasminogen binding to the fibrin surface. The plasma TAFI concentration is almost entirely genetically determined. We investigated whether plasma TAFI levels and polymorphisms located in the TAFI gene could constitute risk markers of myocardial infarction (MI). Plasma TAFI antigen (Ag) levels were assayed by ELISA and 2 TAFI gene polymorphisms (Ala147Thr and C+1542G in the 3' untranslated region) were determined in a large European case-control study. This study compared 598 men recruited 3 to 6 months after MI with 653 age-matched controls from North Europe (Stockholm, Sweden, and London, England) and South Europe (Marseilles, France, and San Giovanni Rotondo, Italy). A TAFI Ag value above the 90th percentile was associated with a significantly lower risk of MI (odds ratio 0.55, P<0.02), indicating that elevated TAFI may be protective against MI. As previously shown, the 2 TAFI gene polymorphisms were in strong linkage disequilibrium and were associated with the TAFI Ag concentration, with carriers of the Thr147 and 1542C alleles having higher levels (P<0.0005). These effects were similar in controls and cases and in each center. There was a difference in allele frequency between cases and controls for the Ala147Thr polymorphism, with Thr147 allele carriers being more frequent in controls than in cases in 2 centers, Stockholm (P=0.03) and San Giovanni Rotondo (P=0.03); the odds ratio for the entire cohort was 0.78 (P<0.05). In conclusion, patients with a recent MI presented lower values of TAFI Ag and higher frequencies of the "TAFI-decreasing" alleles. The geographical differences observed do not contribute to explaining the North-South gradient in MI risk in Europe.

Alleles↗
PubMed2002

Plasma tumour necrosis factor-alpha and early carotid atherosclerosis in healthy middle-aged men.

AIMS: Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine, which is implicated in some metabolic disorders and may play a role in the development of cardiovascular disease. We examined whether plasma TNF-alpha is related to established cardiovascular risk indicators, plasma levels of soluble cellular adhesion molecules and carotid artery intima-media thickness determined by ultrasound examination in a population-based cohort of 96 healthy 50-year-old men. METHODS AND RESULTS: TNF-alpha and cellular adhesion molecules were measured with enzyme-linked immunosorbent assays. Plasma TNF-alpha concentration was associated with systolic and diastolic blood pressure, degrees of alimentary lipaemia, plasma very low density lipoprotein triglyceride, low density lipoprotein (LDL) cholesterol concentrations and peak LDL particle size. Two indices of insulin resistance as well as all soluble cellular adhesion molecules correlated positively with TNF-alpha. The plasma TNF-alpha concentration was associated with common carotid intima-media thickness in univariate analysis. In contrast, soluble E-selectin and postprandial triglycerides, but not TNF-alpha, were independent determinants of common carotid intima--media thickness. CONCLUSION: The plasma TNF-alpha concentration is associated with degrees of early atherosclerosis and correlates with metabolic and cellular perturbations that are considered important for the vascular process.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2002

Cardiac valvular abnormalities are frequent in systemic lupus erythematosus patients with manifest arterial disease.

The objective of this study was to study cardiac valve morphology and function and ventricular function in systemic lupus erythematosus (SLE) patients with and without co-existing cardiovascular disease (CVD) and in population controls. Twenty-six women (52 +/- 8.2 years) with SLE (SLE cases) and a history of CVD (angina pectoris, myocardial infarction, cerebral infarction or intermittent claudication) were compared with 26age-matched women with SLE but without manifest CVD (SLE controls) and 26 age-matched control women (population controls). Echocardiographywas performed to assess valvular abnormalities and manifestations of ischaemic heart disease. Thirteen of the 26 SLE cases but only one of the SLE controls and one of the population controls had cardiac valvular abnormalities. Three of the SLE cases had already undergone valve replacement and another had significant aortic insufficiency; the other nine had thickening of mainly mitral leaflets without hemodynamic significance. Among SLE cases, patients with valvular abnormalities had higher homocysteine (P < 0.001) and triglyceride (P = 0.02) concentrations than patients without valvular disease. In contrast atherosclerosis as determined by IMT, oxidized LDL as measured by the monoclonal antibody E06, autoantibodies against epitopes of OxLDL (aOxLDL) or phospholipids (aPL), disease duration or activity, or acute phase reactants did not differ between SLE cases with or without valvular abnormalities. Valvular abnormalities were not more common in SLE cases with stroke as compared to those with myocardial infarction, angina or claudication. In conclusion, valvular abnormalities are strongly associated with CVD in SLE. Raised levels of homocysteine and triglycerides characterize patients with cardiac valve abnormalities.

Acute-Phase Reaction↗
PubMed2002

Fatty acid binding protein expression in different human adipose tissue depots in relation to rates of lipolysis and insulin concentration in obese individuals.

Two fatty acid binding proteins (FABPs) are expressed in adipose tissue, adipocyte lipid binding protein (ALBP) and keratinocyte lipid binding protein (KLBP). This study investigated FABP expression in visceral and subcutaneous human adipose tissue depots and associations with lipolytic differences between the depots and circulating insulin concentrations. ALBP and KLBP (protein and RNA) were quantified in subcutaneous and omental adipose tissue from obese individuals and expressed relative to actin. ALBP RNA and protein expression was significantly higher in subcutaneous compared to omental adipose tissue (both p < 0.05), whereas KLBP RNA and protein expression was no different between the two sites. There were significant inverse correlations between serum insulin concentrations and the ALBP/KLBP RNA ratio in both subcutaneous and omental adipose tissue (both p < 0.02). Basal rates of glycerol and fatty acid release measured in adipocytes isolated from subcutaneous and omental adipose tissue were significantly higher in the former (p < or = 0.02). Therefore the relative ALBP/KLBP content of human adipose tissue is different in different adipose tissue depots and at the RNA level is related to the circulating insulin concentration, at least in obese subjects. The higher rates of basal lipolysis in adipocytes isolated from subcutaneous compared to omental adipose tissue might be related to the increased ALBP content of the former. Therefore adipose tissue FABPs are interesting candidates for investigation to further our understanding of the insulin resistance syndrome and regulation of lipolysis.

Actins↗
PubMed2001

Risk factors for cardiovascular disease in systemic lupus erythematosus.

BACKGROUND: Cardiovascular disease (CVD) is overrepresented in patients with systemic lupus erythematosus (SLE). We determined the prevalence of traditional and nontraditional risk factors for CVD in SLE patients with and without CVD compared with controls. METHODS AND RESULTS: Twenty-six women (aged 52+/-8.2 years) with SLE and a history of CVD (SLE cases) were compared with 26 age-matched women with SLE but without manifest CVD (SLE controls) and 26 age-matched population-based control women (population controls). Common carotid intima-media thickness (IMT) was measured by B-mode ultrasound as a surrogate measure of atherosclerosis. SLE cases had increased IMT compared with SLE controls (P=0.03) and population controls (P=0.001), whereas IMT of SLE controls did not differ from population controls. SLE cases had raised plasma concentrations of circulating oxidized LDL (OxLDL; P=0.03), as measured by the monoclonal antibody EO6, and autoantibodies to epitopes of OxLDL (P<0.001); dyslipidemia with raised triglycerides (P<0.001) and lipoprotein(a) (P=0.002) and decreased HDL-cholesterol concentrations (P=0.03); raised alpha-1-antitrypsin (P=0.002), lupus anticoagulant (P=0.007), and homocysteine levels (P=0.03); more frequent osteoporosis (P=0.03); and a higher cumulative prednisolone dose (P=0.05) compared with SLE controls. Disease duration, smoking, blood pressure, body mass index, and diabetes mellitus did not differ significantly between the groups. CONCLUSIONS: alpha set of distinct CVD risk factors separate SLE cases from SLE controls and population controls. If confirmed in a prospective study, they could be used to identify SLE patients at high risk for CVD in order to optimize treatment.

Autoantibodies↗
PubMed2001

Human evidence that the apolipoprotein a-II gene is implicated in visceral fat accumulation and metabolism of triglyceride-rich lipoproteins.

BACKGROUND: Apolipoprotein (apo) A-II is a major structural protein of plasma HDLs, but little is known regarding its functions. METHODS AND RESULTS: To investigate the physiological role of apoA-II in humans, we screened the promoter region of the apoA-II gene for a functional polymorphism and used this polymorphism as a tool in association studies. A common, functional polymorphism in the promoter region of the apoA-II gene, a T to C substitution at position -265, was found. Electrophoretic mobility shift assays demonstrated that the -265T/C polymorphism influences the binding of nuclear proteins, whereas transient transfection studies in human hepatoma cells showed a reduced basal rate of transcription of the -265C allele compared with the -265T allele. The -265C allele was associated with decreased plasma apoA-II concentration and decreased waist circumference in healthy 50-year-old men. In addition, oral fat tolerance tests provided evidence that the -265C allele enhances postprandial metabolism of large VLDLs. CONCLUSIONS: ApoA-II appears to promote visceral fat accumulation and impair metabolism of large VLDLs.

Adipose Tissue↗
PubMed2001

Polymorphisms in the thrombopoietin gene are associated with risk of myocardial infarction at a young age.

Five polymorphisms in the thrombopoietin (TPO) gene were identified, one in the 5' untranslated region (UTR) (C1796T), two within intron 5 (C4830A and A4877C), and two in the 3' UTR (A5713G and A6160T). The allele frequencies were determined in a group of 450 healthy middle aged men from the UK and found to be 0.46 for 1796T, 0.38 for 4830A, 0.004 for 4877C, 0.47 for 5713G and 0.07 for 6160T. Genotypes for the three common polymorphisms were determined in a group of 176 young male Swedish survivors of a myocardial infarction (MI) and 186 age-matched controls and a group of 156 young Italian survivors of an MI and 147 age and sex matched controls. In both the Swedish and the Italian studies polymorphisms were found to be associated with increased risk of MI. In the Swedish sample the frequency of 4830A was significantly higher in controls (0.40) compared with patients (0.29) (P=0.003), with an odds ratio for AA homozygotes of 0.48 (0.25-0.92; P=0.03) compared with CC homozygotes. In the Italian sample the frequency of 5713G was significantly lower in controls (0.31) compared with cases (0.40) (P=0.03), with an odds ratio for GG homozygotes of 2.29 (1.08-4.89; P=0.03) compared with AA homozygotes. These risk associations are consistent since 4830A and 5713A show strong allelic association. After adjusting for other measured risk factors the effect on risk was still significant in the Italian sample 2.39 (1.02-5.58), but not in the Swedish sample 0.46 (0.16-1.32). The observation of frequency differences between cases and controls in two independent samples strongly suggests that the TPO gene is involved as a risk factor for developing MI at a young age, but the identified polymorphisms are probably acting as markers for an unidentified functional mutation elsewhere in the gene locus.

Adult↗